Cellular homeostasis is regulated tightly by the activities of many cellular proteins. The subcellular localization and stability of these proteins are critical for their activities. Examples include proteins that are transported into or out of the nucleus by specific receptors through the recognition of nuclear-localization signals (NLS) and/or nuclear export signals (NES). One recently identified NES is a short, hydrophobic, leucine-rich motif that is necessary and sufficient to mediate nuclear export of large carrier proteins and mRNAs. The activity of many cellular transcription factors, oncoproteins, cell cycle regulators, and tumor suppressor proteins has been reported to be regulated by their NES. Interestingly, many viral proteins also utilize the Crm1/Ran-mediated pathway, even though some of these viral proteins are thought to be small enough to passively diffuse through the nuclear pore complex (NPC). The fact that these oncogenic viral proteins have acquired NES activity and modified nuclear export implies that nuclear export may be an efficient target for viral-mediated oncogenesis. We are examining the hypothesis that both the X protein (HBx) of hepatitis B virus (HBV) and core protein (HC-core) of hepatitis C virus (HCV), two major risk factors for hepatocellular carcinoma, may induce neoplastic transformation by altering the Crm1/Ran-mediated pathways. Recently, we discovered that the HBx and HC-core proteins contain functional NESs. Unlike other cellular NES-containing proteins, HBx binds to and sequesters Crm1 in the cytoplasm, thereby modulating Crm1-mediated nuclear export of other cellular proteins including the NFkB/IkBa complex. Similarly, HC-core-mediated activation of the NFkB/IkBa complex also depends on the presence of NESs. These findings suggest that multiple cellular functions associated with HBx or HC-core may be due, in part, to their influence on the Crm1/Ran-mediated pathway. Because Crm1 and its cofactor Ran GTPase also play a key role in mitosis initiation, the inactivation of Crm1 by HBx or HC-core also may induce genomic instability. Currently, we are testing the hypothesis that HBx and HC-core may induce genomic instability through their interactions with the Crm1/Ran complex. Recently, we found that Crm1 colocalizes with centrosomes. Use of a Crm1-specific inhibitor or sequestering of Crm1 in the cytoplasm by the oncogenic HBx protein induces unscheduled centriole splitting and the creation of an increased number of mitotic spindle nucleating centers. Premature splitting results in extra segregated centrioles that may serve as a template to initiate centrosome duplication, leading to supernumerary centrosomes in these cells. This effect is preferentially observed in mitotic cells, regardless of their p53 or p21 status and results in multipolar mitotic divisions. In contrast, an HBx mutant lacking the ability to sequester Crm1 in the cytoplasm does not induce supernumerary centrosomes. These results reveal a novel role for Crm1 in the maintenance of centrosome integrity, and imply that HBx disruption of this process may contribute to HBV-mediated pathogenesis. The above studies led us to generate a novel testable hypothesis that Crm1 may be a common target for viral hepatitis-mediated oncogenicity and provide a foundation for a possible involvement of Crm1 in human carcinogenesis.